The broad, long-term objective of the proposed research is to define the consequence of trisomy 21 (Down syndrome) on transcription (gene expression) and translation. Down syndrome is the most frequently occurring cause of mental retardation known to be associated with a chromosomal abnormality. It is caused by a complete or partial trisomy (triplicate state) of chromosome 21. Individuals with Down syndrome have mental retardation to varying degrees, as well as dozens of other phenotypic abnormalities. It is not known how the trisomy of chromosome 21 causes neurological or other pathological phenotypes. The specific aims are as follows: [1] Perform gene expression profiling with trisomy 21 postmortem cerebrum, cerebellum, and heart samples relative to euploid controls. The purpose of these studies is to test the hypothesis that there is a global up-regulation of gene expression in genes assigned to chromosome 21. Through gene expression profiling and subsequent confirmation studies, we will define specific genes that are differentially regulated in trisomy 21 tissues. [2] Determine the transcriptional profile in lymphoblast cell lines from Down syndrome patients and euploid controls. These patients have been clinically characterized (e.g. with neurobehavioral evaluations and brain imaging) and are classified as having severe or mild forms of Down syndrome. We will test the hypothesis that the severity of the clinical phenotype correlates to the magnitude of gene expression changes. [3] While the first two aims address transcriptional changes, in this aim we test the hypothesis that translation is regulated in Down syndrome. We will perform quantitative immunoblotting of fetal brain and heart as well as lymphoblasts. [4] The mechanisms we study in Down syndrome may be relevant to other aneuploidies. We will determine the transcriptional profile in frozen brain and lymphoblasts from individuals with trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome). These are the other major trisomies compatible with life. We will test the hypothesis that in cells derived from these individuals there is a global up-regulation of the expression of genes assigned to chromosomes 13 and 18, respectively.